Relaxin is a pregnancy hormone discovered in 1926 (Hisaw (1926) Proc. Soc. Exp. Biol. Med. 23: 661-663), based on its ability to relax the public ligament in guinea pig. Mature human relaxin is a hormonal peptide of approximately 6000 daltons known to be responsible for remodelling the reproductive tract before parturition, thus facilitating the birth process. A concise review of relaxin was provided by Sherwood, D. in The Physiology of Reproduction, Chapter 16, “Relaxin”, Knobil, E. and Neill, J., et al. (eds.), (Raven Press Ltd., New York), pp. 585-673 (1988). Relaxin has local autocrine and/or paracrine roles that contribute to connective tissue remodeling at the maternal-fetal interface during late pregnancy and at parturition, including an increase in the expression of the genes, proteins, and enzyme activities of the matrix metalloproteinases interstitial collagenase (MMP-1), stromelysin (MMP-3), and gelatinase B (MMP-9).
Two human gene forms of relaxin have been identified, (H1) and (H2) (Hudson et al. (1983) Nature 301:628-631; Hudson et al. (1984) EMBO Journal 3:2333-2339; U.S. Pat. Nos. 4,758,516 and 4,871,670). Only the H2 form is expressed in corpus luteum. The primary translation product of H2 relaxin is a preprorelaxin consisting of a 24 amino acid signal sequence followed by a B chain of about 29 amino acids, a connecting peptide of 104-107 amino acids, and an A chain of about 24 amino acids.
Although relaxin itself has been well-characterized for a number of years, it's receptor has remained elusive. To date, binding studies have had to rely on crude cellular extracts, which indicated that a specific binding molecule was present, but gave no clue as to its molecular identity. Relaxin binding sites have been reported in the reproductive tract (Kohsaka et al. (1998) Biol Reprod 59(4):991-9), as well as other tissues, including cardiac and other smooth muscle, and specific nuclei in the brain (Tan et al. (1999) Br J Pharmacol 127(1):91-8).
During fetal development, the sexual dimorphic position of the gonads in mammals is dependent on the differential development of two ligaments. In males, growth of the gubernaculum and regression of the cranial suspensory ligament results in transabdominal descent of the testes. Impaired testicular descent (cryptorchidism) is a prevalent congenital abnormality in humans, found in 2% of male births. INSL3, also known as Leydig insulin-like peptide or relaxin-like factor (RLF), is one of the seven relaxin-like genes in humans known to be expressed in Leydig cells of fetal and adult testes as well as in theca and luteal cells of the postnatal ovary (Ivell (1997) Rev. Reprod. 2, 133-8). Male mice mutant for INSL3 exhibit bilateral abdominal cryptorchidism whereas female mice overexpressing INSL3 showed ovary descent and displayed bilateral inguinal hernia. Although INSL3 binds to gubernacular homogenates (Boockfor et al. (2001) Reproduction 122, 899-906) and induces growth of rat gubernaculum in whole organ cultures (Smith et al. (2001) J. Pept. Sci. 7, 495-501), the exact nature of the INSL3 receptor is unknown. A recent study indicated that transgene integration in crsp mice resulted in a 550-kb deletion located upstream of the Brca2 gene, leading to defective testis descent (Overbeek et al. (2001) Genesis 30, 26-35).
The identification and molecular characterization of relaxin receptors is of great scientific and clinical interest. Understanding of relaxin signaling mechanisms mediated by its receptor can provide new approaches for the regulation of relaxin target tissues during pregnant and non-pregnant states.